Abstract 558: Focused IL-12 cytokine delivery enhances function of affinity-tuned and real-time tracked ICAM-1-specific CAR T cells in solid tumors
Authors: Jingmei Hsu, Michael P. Gallagher, Yanping Yang, Eric von Hofe, Yen-Michael Hsu, Koen Van Besien, Thomas Fahey, Jana Ivanidze, Janusz Puc, Karrie Du, Moonsoo Jin
Journal: Cancer Research (2022)

Abstract Engineering CAR T cells to target solid tumors presents numerous challenges. Lack of tumor-specific antigens, high probability of CAR T cell exhaustion, and an often-immunosuppressive tumor microenvironment limit CAR T cell efficacy and outcomes in the clinic. To address these challenges, AffyImmune has developed “Tune &amp; Track” technologies to reduce CAR affinity for antigens with disproportionally high density on tumor cells. Our CAR T cells are selective for tumor cells while leaving normal cells untouched, thereby increasing the therapeutic window and allowing for more physiological T cell killing. CAR T cells are also designed to express Somatostatin Receptor 2 (SSTR2), which allows for tracking in vivo via PET/CT scan using FDA-approved DOTATATE. Our primary CAR design called AIC100 expresses an affinity-tuned variant of LFA-1, which is the natural ligand for Intracellular Adhesion Molecule (ICAM)-1, a molecule that is highly expressed on some cancers. A single dose of AIC100 CAR T cells results in elimination of tumors in mice and significantly improves survival. We have tested the safety and anti-tumor activity of AIC100 in high ICAM-1-expressing animal tumor models including triple-negative breast cancer and gastric cancer. AffyImmune is currently conducting a Phase I study (NCT04420754) to evaluate the clinical efficacy of AIC100 in treating advanced thyroid cancer. After receiving 10 million AIC100 CAR T cells, FDG and DOTATATE imaging revealed preliminary evidence of CAR T expansion in the patient and tumor reduction at multiple lesions. To further optimize affinity-tuned CAR T cell activity within tumors, we are currently developing CAR designs that have the capability to deliver effector cytokines to the tumor microenvironment via a nuclear factor of activated T cells (NFAT)-inducible promoter. Because our CAR T cells are affinity-tuned, off-tumor cytokine secretion is minimized. Our ICAM-1-specific CAR design called AIC1010 releases interleukin (IL)-12 cytokine upon engagement with target antigen within tumors, which induces production of interferon (IFN)-γ from immune cells and surrounding tissues, enhancing not only CAR T cell effector function but also the immune response focused within the tumor microenvironment. AIC1010 CAR T cells demonstrate superior cancer elimination compared to AIC100 CAR T cells in subcutaneous and IP tumor models in mice. We anticipate that cytokine delivery, paired with our “Tune &amp; Track” technology will be widely adaptable to develop potent and safe affinity-tuned CAR T cells against hard-to-treat solid cancers. Citation Format: Jingmei Hsu, Michael P. Gallagher, Yanping Yang, Eric von Hofe, Yen-Michael Hsu, Koen Van Besien, Thomas Fahey, Jana Ivanidze, Janusz Puc, Karrie Du, Moonsoo Jin. Focused IL-12 cytokine delivery enhances function of affinity-tuned and real-time tracked ICAM-1-specific CAR T cells in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 558.